The vascular endothelium in diabetes and its potential as a therapeutic target

Article

Keywords

Endothelium Vasculature Insulin resistance Diabetes 

In addition to functioning as the innermost barrier separating the blood from tissue interstitium, vascular endothelium actively regulates vessel functions by both secreting vasoactive factors and direct coupling to nearby smooth muscle. As arterial and arteriolar function varies depending on their size and location the role played by the endothelium differs accordingly. The conduit arteries mainly regulate arterial plasticity/compliance, the resistance arterioles blood pressure and total blood flow to tissues, the pre-capillary arterioles tissue perfusion and the capillaries exchanges of nutrients, oxygen and hormones between the plasma and tissue interstitium.

Vascular endothelium has long been known to be insulin responsive. Endothelial cells express abundant insulin, insulin-like growth factor I (IGF-I) and the hybrid insulin/IGF-I receptors [1, 2, 3]. At physiological concentrations, insulin binds and activates the insulin receptors exclusively. It exerts its biological actions mainly via two signaling pathways. One proceeds by activation of phosphatidylinositol 3-kinase (PI-3 kinase)/protein kinase B (PKB or Akt) pathway that leads to the phosphorylation of serine 1176 of the endothelial nitric oxide (NO) synthase (eNOS) to increase NO production [4, 5]. NO is a potent vasodilator with important anti-atherosclerotic actions as well. Insulin also signals through the mitogen-activated protein kinase (MAPK) pathway to regulate cell proliferation and production of both the vasoconstrictor endothelin-1 and adhesion molecules [6, 7, 8, 9]. In the insulin sensitive state, insulin fine-tunes vascular functions via balancing its signals through these two signaling pathways to maintain endothelial health, arterial wall compliance, vascular tone and tissue perfusion.

Diabetes causes significant morbidity and mortality to patients by accelerating atherosclerosis in large and medium arteries and injuring the microvasculature thus precipitating classical retinal, renal and neural complications. Mounting evidence has confirmed the central role of endothelial dysfunction, characterized by abnormal vascular reactivity, increased production of reactive oxygen species, decreased NO bioavailability, and altered barrier function, in the pathogenesis of both macro- and microvascular complications of diabetes. This is not surprising as diabetes is associated with a wide variety of metabolic/biochemical disturbances in many tissues and blood vessels play indispensible role in maintaining tissue function by delivering nutrients, oxygen and hormones and removing metabolic products. Thus, the endothelium is exposed to both environmental and endogenous stimuli such as nutrients, cytokines, chemokines, hypoxia and other factors.

Endothelial dysfunction and endothelial insulin resistance co-exist in the state of insulin resistance including metabolic syndrome, obesity and diabetes. Almost all factors that cause metabolic insulin resistance also induce endothelial dysfunction and vascular insulin resistance. The term “vascular insulin resistance” can be misleading in that within endothelial cells resistance to insulin action is pathway selective [10, 11, 12]. While insulin responses through the PI3-kinase/Akt/eNOS pathway are attenuated, its action via the MAPK pathway remains intact or even enhanced in the insulin resistant state. As a result, the net effect of insulin action on the vasculature is increased production of adhesion molecules and ET-1 and decreased production/bioavailability of NO, tilting the balance towards pro-atherogenic and vasoconstrictive responses [11, 13, 14, 15]. Markedly increased insulin concentrations which can accompany metabolic insulin resistance may contribute to this process by activating the IGF-I and/or insulin/IGF-I hybrid receptors. Combined, pathway selective insulin resistance and hyperinsulinema-driven MAPK signaling could handily explain why patients with diabetes have accelerated atherosclerosis and are prone to hypertension and tissue hypoxia (Fig. 1). However, evidence supporting this selective insulin resistance mainly stemmed from in vitro cell culture studies and ex vivo studies using isolated blood vessels. Convincing in vivo evidence remains scant.
Fig. 1

Vascular insulin resistance and its consequences

The effects of insulin on the microvasculature have garnered much attention over the past decade. For insulin to exert its metabolic actions it has to be first delivered to tissue interstitium after it is secreted by the pancreatic β-cells. Vascular endothelium clearly plays a barrier role and actively regulates insulin delivery and thus its action in tissues with continuous endothelium like muscle, brain and adipose tissue. In the case of skeletal muscle, it is the muscle interstitial insulin concentrations, not the plasma insulin concentrations, that correlate closely with insulin’s metabolic action [16]. Evidence from human, animal and cultured cell studies have repeatedly demonstrated that insulin itself actively regulates its own delivery to muscle insterstitium by dilating resistance vessels to increase total blood flow, relaxing pre-capillary arterioles to recruit microvasculature and increase endothelial exchange surface area (microvascular recruitment), and trans-endothelial transport of insulin from the plasma compartment to tissue interstitium [17, 18]. When infused acutely, insulin increases muscle microvascular perfusion within 5–10 min and this action precedes and contributes (up to 40 %) to insulin-stimulated glucose uptake in skeletal muscle [19, 20]. This action is reduced in the presence of metabolic insulin resistance as seen in obese humans, healthy humans given lipid infusions to raise plasma free fatty acid levels as well as in animal models of insulin resistance [21, 22, 23].

Overall, studies from the past two decades have convincingly shown that vascular endothelium is an insulin target and that vascular endothelial dysfunction and vascular insulin resistance play central roles in the pathogenesis of metabolic insulin resistance, organ damage/failure and cardiovascular complications of diabetes. These aggregate findings point to vascular endothelium as a very promising therapeutic target in the prevention and/or management of diabetes and insulin resistance. Reduced endothelial insulin resistance and improved endothelial function in the conduit arteries may reduce macrovascular atherosclerotic complications. In resistance arterioles it could improve blood pressure control. While in the microvasculature it could reduce/prevent microvascular complications and enhance tissue insulin action thus metabolic control.

Currently available glycemic therapies, particularly exercise and insulin sensitization, have shown some salutary effects on endothelial function in patients with diabetes. However, only metformin has demonstrated a positive effect in reducing the clinical macrovascular endpoints in obese patients with type 2 diabetes [24]. None of these therapeutic modalities target specifically the endothelium and the improved endothelial function associated with these therapies is likely secondary to improved glycemic control and perhaps some direct action on the endothelium. Several lines of evidence have shown that factors that in clinical studies improve insulin sensitivity and glycemic control, such as exercise, angiotensin II type 1 receptor blocker, and glucagon-like peptide 1, are able to increase microvascular recruitment and muscle delivery/action of insulin in experimental animals [25, 26, 27]. Whether these effects remain in insulin resistant humans are under investigation. More studies are needed to better understand the mechanisms underlying endothelial insulin resistance and endothelial dysfunction in diabetes and other states of insulin resistance and their exact molecular and cellular roles in the pathogenesis of metabolic insulin resistance and diabetic vascular complications. Undoubtedly this will drive the development of endothelium targeted therapies for prevention of diabetes and the vascular injuries that accompany it and other insulin resistant states.

Notes

Acknowledgements

This work was supported by American Diabetes Association grants 7-07-CR-34, 9-09-NOVO-11 and 1-11-CR-30 and National Institutes of Health grant R01 HL-094722.

References

  1. 1.
    Jialal I, King GL, Buchwald S, Kahn CR, Crettaz M. Processing of insulin by bovine endothelial cells in culture: internalization without degradation. Diabetes. 1984;33:794–800.PubMedCrossRefGoogle Scholar
  2. 2.
    Li G, Barrett EJ, Wang H, Chai W, Liu Z. Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells. Endocrinology. 2005;146:4690–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Dekker Nitert M, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ. IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol. 2005;229:31–7.CrossRefGoogle Scholar
  4. 4.
    Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser1179. J Biol Chem. 2001;276:30392–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Zeng G, Nystrom FH, Ravichandran LV, Cong L-N, Kirby M, Mostowski H, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000;101:1539–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Oliver FJ, de la Rubia G, Feener EP, Lee ME, Loeken MR, Shiba T, et al. Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J Biol Chem. 1991;266:23251–6.PubMedGoogle Scholar
  7. 7.
    Eringa EC, Stehouwer CDA, van Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P. Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol. 2004;287:H2043–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Eringa EC, Stehouwer CDA, Merlijn T, Westerhof N, Sipkema P. Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res. 2002;56:464–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Li G, Barrett EJ, Ko S-H, Cao W, Liu Z. Insulin and insulin-like growth factor-I receptors differentially mediate insulin-stimulated adhesion molecule production by endothelial cells. Endocrinology. 2009;150:3475–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999;104:447–57.PubMedCrossRefGoogle Scholar
  11. 11.
    Eringa EC, Stehouwer CDA, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab. 2007;293:E1134–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr Rev. 2007;28:463–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem. 2002;277:1794–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Potenza MA, Marasciulo FL, Chieppa DM, Brigiani GS, Formoso G, Quon MJ, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol Heart Circ Physiol. 2005;289:H813–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Eringa EC, Stehouwer CDA, Walburg K, Clark AD, van Nieuw Amerongen GP, Westerhof N, et al. Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-α dependence on c-jun N-terminal kinase. Arterioscler Thromb Vasc Biol. 2006;26:274–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Castillo C, Bogardus C, Bergman R, Thuillez P, Lillioja S. Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men. J Clin Invest. 1994;93:10–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011;301:E252–63.PubMedCrossRefGoogle Scholar
  18. 18.
    Barrett E, Eggleston E, Inyard A, Wang H, Li G, Chai W, et al. The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia. 2009;52:752–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, et al. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004;53:1418–23.PubMedCrossRefGoogle Scholar
  20. 20.
    Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S. Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab. 2003;285:E123–9.PubMedGoogle Scholar
  21. 21.
    Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006;55:1436–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Clerk LH, Rattigan S, Clark MG. Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes. 2002;51:1138–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009;94:3543–9.PubMedCrossRefGoogle Scholar
  24. 24.
    UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.CrossRefGoogle Scholar
  25. 25.
    Inyard AC, Clerk LH, Vincent MA, Barrett EJ. Contraction stimulates nitric oxide independent microvascular recruitment and increases muscle insulin uptake. Diabetes. 2007;56:2194–200.PubMedCrossRefGoogle Scholar
  26. 26.
    Chai W, Wang W, Dong Z, Cao W, Liu Z. Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo. Diabetes. 2011;60:2939–46.PubMedCrossRefGoogle Scholar
  27. 27.
    Chai W, Dong Z, Wang N, Wang W, Tao L, Cao W, et al. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes. 2012;61:888–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Endocrinology and Metabolism, Department of MedicineUniversity of Virginia Health SystemCharlottesvilleUSA

Personalised recommendations